Antibacterkl compositions



United States Patent 3,123,527 ANTIEBACTERIAL COMPOSITIONS Myron W.Fisher, Birmingham, Mich, assignor to Parke, Davis & Company, Detroit,Mich, a corporation of Michigan No Drawing. Filed May 2, 1958, Ser. No.732,467 Claims. (Cl. 167-51.5)

This application is a continuation-in-part of my application Serial No.717,300, filed February 25, 1958, now abandoned, which in turn is acontinuation-in-part of my application Serial No. 654,658, filed April24, 1957, now abandoned.

The invention relates to chemotherapeutic agents and to means ofcombatting bacterial infection. More particularly, the inventionconcerns improved sulfonamide compositions having greatly enhancedantibacterial action.

The sulfonamide compounds, now widely employed as antibacterial agents,derive their useful effect from their ability to prevent synthesis ofpteroyl compounds which, it is known, are essential to the growth ofmany species of bacteria. In the treatment of streptococcal,meningococcal, gonococcal' and pneurnococcal infections, the sulfonamidecompounds are currently agents of choice. The course of treatmentordinarily requires the repeated administration of substantial amountsof sulfonamide and in many cases where the regimen has been excessive orunduly prolonged undesirable side effects have been noted. On the otherhand, insufiicient dosage often causes the emergence of resistantpathogenic infection. Consequently, at the present time there is animportant need to provide means for increasing the antibacterialeffectiveness of the sulfonamide compounds and for minimizing oravoiding undesirable side-effects of the type associated with the use ofthese compounds.

I have now found that the activity of sulfonamide compositions againstpathogenic bacterial infection is greatly increased by incorporatingtherewith a quantity in the range from about 0.1 to 20%, preferablyabout 0.1 to 1%, bv weight of a dihydrotriazine compound of formula,

NH; j

I OH: N N INHQ where X is a 3-chlorophenyl, 3,5-dichloropheny1,3,5-dibromophenyl or 3-trifluoromethylphenyl radical.

In the compositions of the invention, the antibacterial effect of thesulfonamide and the dihydrotriazine is synergistic, i.e., their combinedantibacterial effect is greater than the summation of their individualeffects. As near as I have been able to determine, the optimum ratio ofsulfonamide to dihydrotriazine is, in general, about 100:1. However, inthe case of 3-sulfanilamido-6-methoxy-pyridazine the optimum ratioappears to be about 50 to 100 parts of the sulfonamide to 1 part of thedihydrotriazine. At these ratios the effectiveness of the sulfonamidecompounds is in general increased fiveto ten-fold.

Thus, means are provided in accordance with the invention of eifectivelycombatting pathogenic bacterial infection with a relatively lesserquantity of therapeutic agent thereby obtaining greater freedom fromundesirable side effects. Conversely, for a given quantity oftherapeutic agent the invention provides greater antibacterial effect.Also, the invention permits more accurate control in dosage and ashorter course of treatment with less inconvenience to the patient.

The invention contemplates broadly the use of sulfonamide compoundswhich per se are effective in combatting 3,123,527 Patented Mar. 3, 1964"ice pathogenic bacterial infection and which are suitable for oraladministration. In general, the sulfonamide compounds contemplatedpossess in common the structural As an illustration of some of the manysulfonamide compounds to which the invention is applicable, there may bementioned sulfacetamide, sulfadiazine, sulfamerizine, sulfarnethazine,sulfathiadiazole, sulfisoxazole, sulfathiazole, p-nitrosulfathiazole,phthalysulfathiazole, salicyazo sulfapyridine, suceinylsulfathiazole,3-sulfanilamido-6- methoxypyridazine and the like. Suitable derivativesof the sulfonamides such as amine salts or metal salts may also beemployed. The invention also contemplates compositions containing morethan a single sulfonamide compound, particularly compositions containingtriple-sulfa combinations such as the combination of sulfacetamide,sulfadiazine and sulfamerizine and similar combinations.

The dihydrotriazines of the present compositions possess basicproperties and form addition salts with acids. The inventioncontemplates the use of the dihydrotriazines not only in free base formbut also in salt form such as the hydrohalide, sulfate, phosphate,acetate and the like. The hydrochloride salt is particularly useful inthat it possesses increased water-solubility and is readily obtainablein pure form.

The compositions of the invention can be conveniently provided byphysically mixing the sulfonamide and dihydrotriazine in theaforementioned proportions, either in dry form or in the form of asuspension in a suitable liquid vehicle. Conveniently, the dry mixturecan be incorporated with granulating and tableting agents such asstarch, magnesium stearate and the like and compounded in tablet form.The dry mixture can also be made up in powder form together with aninert diluent such as talc, starch, milk, sugar and the like, and, ifdesired, filled into gelatin capsules. When supplied as suspensionssuitable for pediatric or other use suspending agents, flavors andstabilizing agents may be employed. Optionally, where a wideranti-bacterial effect is desired, a broad spectrum antibiotic such aschloramphenicol, oral penicillin and the like may be included in theformulation.

In administering the compositions of the invention, the course oftreatment conveniently includes an initial oral dosage of about 15 tomilligrams per kilogram over a twenty-four hour period followed by adaily oral dosage of about 10 to 100 milligrams per kilogram for as longas required. In the case of compositions containing3-sulfanilamido-G-methoxypyridazine, the recommended dosage is 15mg./kg. initially followed by 5-10 mg./kg. daily thereafter. It will beunderstood that the dosage regimen can be varied, as desired, to meetthe particular circumstances of each case depending on the severity ofinfection, etc.

The preparation of compositions in accordance with the invention isillustrated by the following examples:

Example 1 A mixture consisting of 167 g. of sulfadiazine, 167 g. ofsulfamerazine, 167 g. of sulfacetamide and 25 g. ofl-m-trifluoromethylphenyl-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride is blended and the mixture is wettedwith a 10% starch paste. The wet mass is granulated through anoscillating No. 6 stainless steel screen. The resultant product is driedfor 16 hours .at F. and reduced to granulations passing a No. 14

stainless steel screen. The dry granulation is mixed with 3 g. ofmagnesium stearate and 50 g. of starch. The resulting mixture, suitablefor formation into tablets, is

processed through a tableting machine to provide ap proximately 975tablets in diameter each containing 0.5 g. total sulfonamide and 25 mg.of l-m-trifluoromethylphenyl-4,6-diaminol,2-dihydro-2,2-dirnethyl-1,3,5- triazine monohydrochloride.

The 1 mtrifluoromethylphenyl-4,G-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazinemonohydrochloride is prepared in the following manner:

A mixture consisting of 39.3 g. of m-aminobenzotrifluoride, 16.8 g. ofdicyanidiamide, 26 ml. of concentrated hydrochloric acid (36%) and 300ml. of acetone is placed in a 500 ml. flask and stirred at 20-25 C.Three crops of the desired product,1-m-trifluoromethylphenyl-4,6-diamino-l,2,-dihydro-2,2-dimethyl-1,3 ,5-triazine hydrochloride, are removed by filtration from the reactionmixture at intervals of one week, two weeks and three weeks. The productis purified by recrystallization from alcohol; M.P. 19l-193 C.

Example 2 A mixture consisting of 500 g. of sulfadiazine, and 25 g. ofl-(3,5-dibromophenyl)-4,6-diamino-l,2-dihydro-2,2-dimethyl-l,3,5-triazine monohydrochloride is blended and wetted with 10%starch paste. The resultant mass is processed and tableted as in Example1 to provide 970 tablets each containing 0.5 g. of sulfadiazine and 25mg. ofl-(3,5-dibromophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazinemonohydrochloride. The 1-(3,5-diblromophenyl -4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3 S-triazine monohydrochloride (MP. 196197C.) is pre pared as follows:

A mixture of 57.5 g. of 3,5-dibromoaniline hydrochloride, 0.22 mol. ofdicyandiamide and 600 ml. of npropanol is stirred and refiuxed for fivehours. The reaction mixture is cooled, filtered and the filter cakeconsisting of dibromophenylbiguanide hydrochloride is washed with 50l00ml. of n-propanol to remove any trace of color present. A mixture of18.6 g. of dibromophenylbiguanide hydrochloride, 250 ml. of acetone, 100ml. of methanol and 0.01 mol. of hydrogen chloride in 4 N isopropanolsolution is refluxed with stirring for 12 hours, cooled and filtered.Anhydrous ether (300 ml.) is added to the filtrate and thel-(3,5-dibromophenyl)-4,6-diamino-l,2dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride whichseparates is collected and dried; M.P. ZOO-201 C. The product can bepurified by trituration in isopropanol and recrystallization frommethanol.

Example 3 A mixture consisting of 500 g. of sulfaisoazole and 100 g. of1-m-chlorophenyl-4,6-diamino-1,2-dihydro-2,2- dimethyl-1,3,5-triazinemonohydrochloride is blended, compounded and tableted in accordance withthe procedure of Example 1. Approximately 980 tablets each containing0.5 g. of sulfaisoazole and 0.1 g. of l-mchlorophenyl 4,6 diamino 1,2dihydro-2,2-dimethyl- 1,3,5-triazine monohydrochloride are obtained. Thepreparation of the dihydrotriazine is accomplished in the same mannerset forth in Example 1 for the preparation of the trifluoromethylphenyldihydrotriazine, starting with 38.2 g. of m-chloroaniline, 16.8 g. ofdicyandiamide, 26 ml. of concentrated hydrochloric acid and 300 ml. ofacetone.

Example 4 A mixture consisting of 500 g. of sulfathiazole and 5 g. of l-(3 ,5 -dichlorophenyl) -4,6-diamino-l,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride is processedand tableted as in Example 1. The yield is approximately 960 tabletseach containing 0.5 g. of sulfathiazole and 5 mg. of1-(3,5-dichlorophenyl)-4,6-diamino-1,2-dihydro- 2,2 dimethyl 1,3,5triazine monohydrochloride. The preparation of the dihydrotriazineingredient can be accomplished in the manner set forth in Example 2 forthe preparation of the dibromophenyl dihydrotriazine, starting 4 with amixture of 39.8 g. of 3,5-dichloroaniline hydrochloride, 0.22 mol. ofdicyandiamide and 400 ml. of n-propanol and proceeding in the secondstep with 14.1 g. of dichlorophenylbiguanide hydrochloride, 250 ml. ofacetone, ml. of methanol, and 0.01 mol. of hydrogen chloride in 4 Nisopropanol solution.

Example 5 A mixture consisting of 100 g. of sulfadiazine, 100 g. ofsulfamerazine, 100 g. of sulfacetamide and 15 g. of 1 mtrifluorornethylphenyl 4,6 diamino 1,2dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride is blended andfilled into #1 hard gelatin capsules by standard encapsulatingprocedures. Approximately 980 capsules are obtained, each capsulecontaining 0.3 g. total sulfonamide and 15 mg. of1-m-trifiuoromethylphenyl-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride.

Example 6 A mixture consisting of 83.33 g. of 3-sulfani1amido-6-methoxypyridazine, 1.67 g. of l-(3,5-dibromophenyl)- 4,6 diamino 1,2dihydro 2,2 dimethyl 1,3,5 -triazine monohydrochloride, 2.5 g. ofalginic acid and 4 g. of corn starch is blended and then wetted with anaqueous paste containing 8.17 g. of corn starch, 2.17 g. of gelatin,0.033 g. of tartrazine (trisodium salt of 3-carboxy-5-hydroxy 1 psulfophenyl 4 p sulfophenylazopyrazole) and 0.013 g. of Orange G(disodium salt of l-phenylazo-2-naphthol-6,8-disulfonic acid). Themixture is granulated through an oscillating No. 6 stainless steelscreen and the resulting granulation dried at F. for sixteen hours. Themixture is reduced to a particle size suitable for compressing (No. 14screen) and 0.5 g. of magnesium stearate blended into the granulation.The resulting mixture processed through a tableting machine to provideabout quarter scored tablets inch in diameter each containing 0.5 g. of3-sulfanilamido-6-methoxypyridazine and 10 mg. of1-(3,5-dibromophenyl)-4,'6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazinemonohydrochloride.

If one employs 0.84 g. of l-(3,5-dibromophenyl)-4,6-diamine-l,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride in theabove procedure instead of the 1.67 g. one obtains tablets which contain0.5 g. of 3-sul'fanilamido- 6-methoxypyridazine and 5 mg. ofl-(3,5-dibromophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,S-triazine.

Example 7 A mixture consisting of 300 g. of finely divided3-sulfam'lamido-S-methoxypyridazine, 6 g. of finely divided 1- (3,5dibromophenyl) 4,6 diamino 1,2 dihydro- 2,2-dimethyl-1,3,5-triazinemonohydrochloride and 30 g. of milk sugar is blended and filled into #2hard gelatin capsules so that each capsule contains 0.5 g. of3-sulfanilarnido-6- methoxy-pyridazine and 10 mg. 1-(3,5-dibromophenyl)4,6 diamino 1,2 dihydro 2,2 dimethyl-1,3,5-triazine monohydrochloride.

If desired, an equal Weight of 1-(3-chlorophenyl)-4,6-diamino-l,2-dihydro-2,2-dimethyl-1,3,5-triazine, 1-(3,5-dichlorophenyl)4,6 diamino 1,2 dihydro 2,2 dimethyl-1,3,5-triazine,l-(3-trifluoromethylphenyl) 4,6-diamino-l,2-dihydro-2,2-dirnethyl-1,3,5-triazine or an acid additionsalt thereof, such as the hydrochloride salt, can be substituted for the1-(3,5-dibromophenyl)-4,6-diamino- 1,2 dihydro 2,2 dimethyl 1,3,5triazine monohydrochloride used in the above example.

Example 8 A mixture consisting of 300 g. of finely divided3-sulfanilamido-6-methoxypyridazine, 300 mg. of finely divided 1 (3,5dibromophenyl) 4,6 diamino 1,2 dihydro- 2,2-dimethyl-1,3,5-triazinemonohydrochloride and 30 g. of milk sugar is blended and filled into #2hard gelatin capsules so that each capsule contains 0.5 g. of 3-sulfa-.5 hilamido-G-methoxypyridazine and 0.5 mg. of 1-(3,5-dibromop henyl) i4,6 diamino 1,2 dihydro 2,2 dimethyl-1,3,5-triazine monohydrochloride.

If similar preparations containing another triazine are desired, anequal weight of 1-(3-chlorophenyl)-4,6-diamino 1,2 dihydro 2,2 dimethyl1,3,5 triazine, 1 3,5 dichlorophenyl) 4,6 diamino 1,2 dihydro-2,2-dirnethyl-1,3,5-triazine or l-(3-trifluoromethylphenyl)- 4,6 diamino1,2 dihydro 2,2 dimethyl 1,3,5 triazine, or an acid addition salt of anyof these mentioned triazines, such as the hydrochloride salt, can besubstituted for thel-(3,5-dibromophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazinemonohydrochloride used above. Likewise, the mentioned3-sulfanilamido-6-methoxy-pyridazine used above can be replaced with alike amount of any of sulfadiazine, sulfaisoxazole or sulfathiazole orwith a 300 g. quantity of equal amounts of each of sulfadiazine,sulfamerazine and sulfacetamide.

Example 9 i A mixture consisting of one kilogram each of sulfadiazine,sulfamerazine and sulfacetamide and 30 g. of l m trifiuoromethylphenyl4,6 diamino 1,2 dihydro-2,2-dimethyl1,3,5-triazine monohydrochloride isblended, wetted with 10% starch paste and granulated, while wet, througha stainless steel No. '6 mesh screen. The granulated product is dried byholding for 16 hours at 140 F. and then subdivided to pass a No. 14stainless screen. The dry granulation is mixed with 20 g. of magnesiumstearate and 300 g. of starch to provide a mixture suitable forcompression into tablets. The mixture is processed through a inchtableting machine to provide about 5650 tablets each containing ca. 0.5g. total sulfonamide and 5 mg. of1-m-trifluoromethylphenyl-4,6-diamino-l,2-dihydro-2,2-dimethyl-1,3,5-triazinemonohydrochloride.

While in the foregoing specification the invention has been described indetail, it will be realized by those skilled in the art thatconsiderable variation can be made in such detail without departing fromthe spirit of the invention as set forth in the appended claims.

I claim:

1. An antibacterial composition comprising a sulfonamide havingantibacterial activity and a member of the class consisting of adihydrotriazine and acid salts thereof, said dihydrotriazine having infree base form the formula,

| NHz where X is a member of the group consisting of 3-chlorophenyl,3,5-dichlorophenyl, 3,5-dibromophenyl and 3-trifluorornethylphenyl, theweight ratio of said sulfonamide and dihydrotriazine being in the rangefrom about 1000:1 to :1.

2. A therapeutic composition in dosage unit form adapted for oraladministration comprising 1000 parts by weight of a sulfonamide havingantibacterial activity and from about 1 to 200 parts by weight of amember of the class consisting of a dihydrotriazine and acid saltsthereof, said dihydrotriazine having in free base form the formula,

6 where X is a member of the group consisting of 3-ch 1orophenyl,3,5-dichlorophenyl, 3,5-dibromophenyl and 3-trifluoromethylphenyl.

3. A composition according to claim 2 wherein the weight ratio ofsulfonamide to dihydrotriazine is 100:1.

4. A therapeutic composition in dosage unit form adapted for oraladministration comprising 100 parts by weight of substantially equalportions of sulfadiazine, sulfamerazine and sulfacetamide and one partof l-m-trifluoromethylphenyl-4,6-diamino-1,2-dihydro-2,2dimethyl-1,3,5-triazine hydrochloride.

5. An antibacterial composition comprising3-sulfanilamido-6-methoxypyridazine and a dihydrotriazine of the classconsisting of l-(3-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-

dimethyl-1,3 ,5 -triazine;

1-(3,5-dichlorophenyl) -4,6-diarnino-1,2-dihydro-2,2-

dimethyl-1,3 ,5 -triazine;

1(3,5-dibromophenyl) -4,6-diamino-1,2-dihydro-2,2-

dimethyl-1,3 ,5 -triazine;

1-(3-trifluoromethylpl1enyl) -4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

and acid salts thereof, the Weight of said B-sulfanilamido-6-methoxy-pyridazine and said dihydrotriazine being in the range of from1000:1 to 5:1.

6. A tablet comprising 50 to 100 parts by weight of 3-sulfanilamido-6-methoxypyridazine for each part by Weight of1-(3,5-dibromophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazinemonohydrochloride.

7. A capsule containing a mixture comprising 50 to 100 parts by weightof 3-sulfanilamido-6-methoxy-pyridazine for each part by weight of1-(3,5-dibromophenyl)- 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,S-triazine monohydrochloride.

8. The method of combatting pathogenic bacterial infection whichcomprises administering orally a composition in dosage unit formcontaining 1000 parts by weight of a sulfonamide having antibacterialactivity and from about 1 to 200 parts by weight of a member of theclass consisting of a dihydrotriazine and acid salts thereof, saiddihydrotriazine having in free base form the formula,

NHa

where X is a member of the group consisting of 3-chlorophenyl,3,5-dichlorophenyl, 3,5-dibromophenyl and 3-trifiuoromethylphenyl.

References Cited in the file of this patent UNITED STATES PATENTS2,484,175 Lehr Oct. 11, 1949 2,599,145 Vogel June 3, 1952 2,602,038Vollmer July 1, 1952 (Other references on following page) 7 FOREIGNPATENTS Chemical Age, April 23, 1949, vol. 60, pp. 592 and 5 Hayman:Amer. 1. Pharmacy, vol. 122, No. 2, February 1950, pp. 72-74.

Welch et 211.: Comparison of Effects of Nine Antibiotics on ExperimentalTyphoid Infections in Mice,

Jour. Lab. and Clin. Med., May 1950, vol. 35, No. 5, pp. 663-666.

Hawking et a1.: The Sulphonamides, H. K. Lewis C0., London, 1950, pp.61-64.

Chem. Abstn, v01. 48 (1954), p. 79.6.

Chem. Abstn, v01. 48 (1954), p. 7189.

Wilson et 211.: The American Drug Index, I. B. Lippincott C0., Phila.,1956, pp. 148, 175, 251, 352353, and 487.

8. THE METHOD OF COMBATTING PATHOGENIC BACTERIAL INFECTION WHICHCOMPRISES ADMINISTERING ORALLY A COMPOSITION IN DOSAGE UNIT FORMCONTAINING 1000 PARTS BY WEIGHT OF A SULFONAMIDE HAVING ANTIBACTERIALACTIVITY AND FROM ABOUT 1 TO 200 PARTS BY WEIGHT OF A MEMBER OF THECLASS CONSISTING OF A DIHYDROTRIAZINE AND ACID SALTS THEREOF, SAIDDIHYDROTRIAZINE HAVING IN FREE BASE FORM THE FORMULA,